Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza.
Wang Y., Zhong W., Salam A., Tarning J., Zhan Q., Huang J-A., Weng H., Bai C., Ren Y., Yamada K., Wang D., Guo Q., Fang Q., Tsutomu S., Zou X., Li H., Gillesen A., Castle L., Chen C., Li H., Zhen J., Lu B., Duan J., Guo L., Jiang J., Cao R., Fan G., Li J., Hayden FG., Wang C., Horby P., Cao B.
<h4>Background</h4>The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19.<h4>Methods</h4>In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (C<sub>trough</sub>) ≥20 mg/L at all measured time points after the second dose.<h4>Results</h4>Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir C<sub>trough</sub> decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved C<sub>trough</sub> ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza.<h4>Conclusion</h4>The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.